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The increasing number of DNA polymorphisms characterized in humans will soon allow the construction of fine genetic maps of human chromosomes. This advance calls for a reexamination of current methodologies for linkage analysis by the family method. We Just as molecular hybridization has given a new power to methods for physical assignments (1), the new wealth of DNA polymorphisms (2, 3) will elicit the development of new strategies for linkage analysis by family methods. When only about 30 genetic markers were available at arbitrary locations, affording a very partial coverage of the human genome, a natural approach for the detection of linkage between a disease locus and a battery of markers consisted in the pairwise analysis of the disease phenotype and each marker in turn. Two-locus linkage analysis by the now classical method of lod-scores (4) or related techniques was originally restricted to simple Mendelian traits and nuclear families; later it was extended to complex phenotypes and general pedigrees through the development of appropriate algorithms and computer programs (5-7).More than 200 DNA polymorphisms have been defined in recent years (8), and there is no doubt that the number required to span the human genome (2, 9) will be reached soon.This inevitably raises questions regarding the relative merits of two-point and multipoint linkage analysis. Although the advantages of multipoint tests, as opposed to pairwise tests, seems generally intuitive (10), a systematic investigation is necessary before new approaches can be proposed.Need for a multilocus analysis is evident for the calculation of genetic risks when several linked markers are available; otherwise there would be no general way of combining pedigree calculations involving each marker singly. For detection of linkage, estimation of recombination, and construction of genetic maps, the merit of multipoint tests has yet to be established. Although Meyers et al. (11) considered three-point tests in restricted situations, most procedures for estimation of recombination and genetic mapping in humans have been based on the assumption that results from independent two-point linkage tests are combined (12)(13)(14).The determination of a genetic map from results of linkage analyses requires assumptions about the mathematical relationships between map distance, expressed in units of crossing-over, or morgans, and recombination frequency, thus defining a mapping function. This relation is complex because recombination results from an odd number of points of exchange between loci, and evidence points to their nonindependence-i.e., interference in crossing-over (15). Various mapping functions have been proposed embodying specific assumptions regarding interference (15). Statistical methods have been proposed that assume a mapping function or a specific process of chiasma formation (12)(13)(14) or that infer a genetic map solely from the rank-order constraints implied by pairwise recombination estimates (16).As the genetic map is developed, it is...

In earlier studies, we provided statistical evidence that individual differences in the angiotensinogen gene, the precursor of the vasoactive hormone angiotensin II, constitute inherited predispositions to essential hypertension in humans (1). We have now identified a common variant in the proximal promoter, the presence of an adenine, instead of a guanine, 6 bp upstream from the initiation site of transcription, in significant association with the disorder. Tests of promoter activity and DNA binding studies with nuclear proteins suggest that this nucleotide substitution affects the basal transcription rate of the gene. These observations provide some biological insight about the possible mechanism of a genetic predisposition to essential hypertension; they may also have important evolutionary implications. ( J. Clin. Invest. 1997. 99:1786-1797.)

Abstract-The renin-angiotensin system is a major regulator of body sodium, predominantly through the actions of intrarenal angiotensin II of unclear origin. We show that polarized epithelium of the proximal tubule synthesizes and secretes angiotensinogen at its apical side and that the protein can be detected in urine as a function of dietary sodium. Furthermore, we demonstrate that renin is expressed and secreted in a restricted nephron segment, the connecting tubule, also in a sodium-dependent fashion. A paracrine renin-angiotensin system operating along the entire nephron may contribute to long-term arterial pressure regulation by integrating distant tubular sodium-reabsorbing functions.(Hypertension. 1999;34:1265-1274.)